Staphylococcus aureus is responsible for the vast majority of skin infection in humans, which corresponds to 14 million outpatient visits and nearly 500,000 hospital admissions per year in the U.S. Moreover, the epidemic of community-acquired methicillin-resistant S. aureus (CA-MRSA) infections in the past 2 decades has become a serious public health concern, as virulent and multi-drug resistant strains are causing severe and recurrent skin infections in healthy people outside hospital settings. If future immunotherapies and vaccines are to provide an alternative to antibiotics, understanding the cutaneous host defense mechanisms that protect against S. aureus skin infections is essential. In humans, patients with loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) (i.e., hyper-IgE syndrome patients [HIES]) have a deficiency of circulating T helper 17 cells (Th17 cells) and suffer from recurrent S. aureus skin infections. These findings suggest that STAT3 and Th17 cells are important for immune protection against S. aureus skin infections in humans. The role of STAT3 in Th17 responses complex as cytokines that signal via STAT3 (IL-6, IL-23) are thought to promote the generation of Th17 cells (as well as Th22 and IL-17/IL-22-producing ?? T cells) and effector cytokines that signal via STAT3 (IL-6, IL-21 and IL-22) are produced by these cells. Therefore, we used an in vivo mouse model of a CA-MRSA in conjunction with STAT3 cre/lox conditional knockout mice to investigate STAT3-mediated responses among resident skin cells, trafficking of immune cells (including neutrophil recruitment/abscess formation that is crucial for immunity against S. aureus infections) and the development of T cell responses. In our preliminary data, we found that deletion of STAT3 in T cells and especially in keratinocytes resulted in markedly impaired S. aureus bacterial clearance. The host defense role of STAT3 in keratinocytes is a novel finding because it provides an explanation for the contradiction of why S. aureus infections are confined to the skin in HIES patients despite the presence of a systemic deficiency in Th17 cells. Based on these findings, our overall hypothesis is that STAT3 signaling in keratinocytes and T cells interact to promote antimicrobial peptide production, neutrophil recruitment and generation of IL-17/IL-22-producing ?? T cells and Th17/Th22 cells for optimal host defense against S. aureus skin infections. This study has three aims. Aim 1 will evaluate the host defense role of STAT3 in keratinocytes, Aim 2 will evaluate the differential role of STAT3 in T cell subsets, and Aim 3 will evaluate the host defense role of STAT3 in human skin grafts and keratinocytes against S. aureus. The insights gained in this proposal will provide more effective immune mechanisms to target in the future development of immunotherapies and vaccines against S. aureus skin infections in humans.